Dahinden, C.

Fehr, J.

Russi, R.

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160 CorrespondenceLegend. Female New Zealand White rabbits of 2.0-2.5 kg weight were prepared for induction of left-side bacterial endocarditisas previously described [1], with the polyethylene catheter left in place throughout the experiment. After placement of the catheterrabbits were randomly assigned to receive either antibiotic therapy or no treatment. Forty-eight hours after placement of the catheterprophylactic therapy was begun. All animals in the treatment groups were given N-formimidoyl thienamycin 15-20 min before theiv injection of 1 ml of an 18 hr culture of the test organism. Groups of treated animals were then assigned to receive one, two,or three additional doses of antibiotic every 2.5 hr after infection. Each dose was of 33 mg N-formimidoyl thienamycinlkg bodyweight, given sc. Forty-eight hours after the last dose of antibiotic, animals were killed, vegatations were excised, weighed, andhomogenized in 2.0 ml of brain-heart infusion (BHI) broth. Undiluted homogenate and lO-fold dilutions were incorporated into20 ml BHI-agar pour plates in duplicate. After incubation at 37 C for 48 hr, the number of cfu/g of vegetation was calculated.Positive vegetations were defined as ~1 cfu recovered from the vegetation.Inocula of 1 ml of organisms (numbers shown in table) were prepared from 18 hr cultures in BHI broth. Four stains of Streptococcusfaecalis were used; two (EBC-2 and EIR, kindly provided by R.C. Moellering, Jr.) were streptomycin-resistant (>6,400 lig/ml) andtwo (B-9 and 4037) were streptomycin-susceptible. Two strains of Staphylococcus aureus were tested, one of which (Berman) wasmethicillin-resistant (>100 lig/ml). Two strains of Streptococcus sanguis and one strain of Streptococcus intermedius were also evaluated.Mortality during the course of the experiment occurred only in the untreated animals infected with S. aureus strains (50070 for eachstrain) and in one untreated animal inoculated with S. sanguis I. MIC and MBC for N-formimidoyl thienamycin against each strainwas ascertained with the macrodilution technique.--=-----------------------------------Number of doses of antibioticOrganism MIC/MBC(inoculum/ml) <lig/ml) I (Preinfection) 2 3 4 No treatmentStreptococcus faecalisStrain B-9 (1.2 x 107) 0.78/~50 2/8 1/7 0/7 0/7 9194037 (1.1 x 107) 0.78/~50 2/7 1/9 8/8EBC-2* 0.3 x 107) 0.78/~50 1/8 0/8 0/7 0/7 7/7EIR* (1.0 x 107) 0.78/~50 2/9 019 10/10Staphylococcus aureus4/4tStrain 2776 (2.6 x 106) 0.05/0.20 4/8 0/8 1/8 0/8Bermant (1.3 X 106) 1.561100 019 OlIO 5/5tOther Streptococcus speciesS. sanguis I (2.6 X 107) 0.1010.20 919 8/8 6/8 6/7 7/7S. sanguis II (1.5 X 107) 0.1010.39 1/7 1/8 0/8 0/8 8/8S. intermedius (7.9 X 107) 0.10/0.39 5/6 6/7 5/7 3/7 8/8S. intermedius (1.7 x 107)(repeat of above strain) 8/8 6/7 6/7 5/8 919* Streptomycin-resistant.t Methicillin-resistant.t Culture of li.ve animals only; 50% mortality prior to sacrifice.References1. Durack DT, Starkebaum MK, Petersdorf RG. Chemotherapy of ex-perimental streptococcal endocarditis. VI. Prevention of enterococ-cal endocarditis. J Lab Clin Med 1977;90:171-92. Guze PA, Kalmanson GM, Freedman LR, Ishida K, Guze LB. Anti-biotic prophylaxis against streptomycin-resistant and -susceptibleStreptococcus jaecalis endocarditis in rabbits. Antimicrob AgentsChemother 1983;24:514-73. Hess J, Dankert J, Durack D. Significance of penicillin tolerance invivo: Prevention of experimental Streptococcus sanguis endocardi-tis. J Antimicrob Chemother 1983;11:555-64THE JOURNAL OF INFECTIOUS DISEASES. VOL. 150, NO.1. JULY 1984© 1984 by The University of Chicago. All rights reserved. 0022-1899/84/5001-0030$1.00Formylated Chemotactic Peptides Can Mimic theSecondary, Provoking Endotoxin Injection in theGeneralized Shwartzman ReactionCOLLEAGUES: The generalized Shwartzman reaction, the toxicreaction that occurs when two sequential iv injections of endo-Please address requests for reprints to Dr. J. Fehr, Clinical Hematol-ogy, Department of Medicine (Clinic) CH5, University Hospital,Ramistrasse 100, CH-8091 Zurich, Switzerlandtoxin are given 24 hr apart, is a powerful, although still enig-matic animal model with which to study the plethora of in vivobiologic effects of endotoxin. It is known that the preparativestate can be brought about in ways and by agents other than byendotoxin (i.e., pregnancy, pretreatment with corticosteroids)and it has recently been shown that staphylococcal pyrogenicexotoxin C dramatically enhances host susceptibility to lethalshock caused by endotoxin [I]. For these reasons we addressedourselves to the question of whether N-formyl methionyl pep-tides that represent synthetic analogues of granulocyte-activat-Correspondence 161Legend. Experiments on possible interchangeability of endotoxin and N-formylated methionine-leucine-phenylalanine (fMLP) inthe generalized Shwartzman reaction.Animal groups Preparative injection Provocative injection No. dead/total no.(rabbits) (neutropenia)* (neutropenia) of rabbits treatedA Endotoxin (p*) Endotoxin (p) 3/3B fMLP (t) Endotoxin (p) 0/8tC Endotoxin (p) fMLP (p) 6/9tD fMLP (t) fMLP (t) 0/3NOTE. Rabbits that weighed 3-4 kg were anesthetized with Hypnorm® (Philips Duphar, Amsterdam). Endotoxin (Escherichiacoli 026.B6; Difco, Detroit), 380 IJg/kg of body weight, and fMLP (Bachem AG, Bubendorf, Switzerland), 2 IJmol/animal, wereadministered through ear. veins. Blood for granulocyte counts was drawn from the carotid artery through an inserted cannula at0, 15,60, and 120 min. Animals died in less than 12 hr. The results in group D confirm eight years of personal experience of fMLPinjections into rabbits.* p = persistent neutropenia (circulating granulocytes remained below 15% for more than 120 min); t = transient neutropenia(circulating granulocytes were below 15010 at 15 min, reached pre-injection values at 60 min, and were overshooting at 120 min).t Mortality between groups Band C is significantly different (P < .01 by Fisher's exact t test).ing bacterial products [2] (as distinct from lipopolysaccharides)might act as substitutes for either the preparative or the pro-vocative injection of endotoxin. The main rationale for per-forming these experiments was that both endotoxin and for-mylated peptides provoke a precipitous and profound fall in thenumber of circulating granulocytes. Our results clearly showthat N-formylated methionine-leucine-phenylalanine (fMLP) isa deleterious substance in animals that have been prepared withendotoxin. In contrast, preparation of animals with fMLP doesnot induce increased susceptibility to endotoxin. The mecha-nisms responsible for this phenomenon are presently unknown.Since endotoxin and fMLP possess similar granulocyte activat-ing potencies [3], we suggest that endotoxin-induced endothe-lial damage may play an essential role: if fMLP-activated, hy-peradhesive [4] granulocytes encounter endothelial cells thathave been injured by endotoxin (an injury that does not occurwith fMLP alone), the result is a deleterious sequence of events(e.g., persistent neutropenia; see table). In contrast, if granulo-cytes activated by either endotoxin or fMLP encounter native,undamaged endothelium, subsequent alterations remain limited.In conclusion, our results show that endotoxin and otherbacterial products can have a pathomechanistic role in enhance-ment of susceptibility to lethal endotoxin shock. If similar in-terchangeability of endotoxin and fMLP analogues are realizedin humans, stimulator-directed therapeutic interventions maybe desirable. Phenylbutazone has been recognized as a specificand clinically applicable antagonist for fMLP-activation ofgranulocytes [4], so effective intervention may be feasible.J. FEHR, C. DAHINDEN, R. RUSSIUniversity Hospital, Zurich, SwitzerlandReferences1. Schlievert PM. Enhancement of host susceptibility to lethal endo-toxin shock by staphylococcal pyrogenic exotoxin type C. InfectImmun 1982;36:123-82. Schiffmann E, Corcoran BA, Wahl SM. N-formylmethionyl peptidesas chemoattractants for leukocytes. Proc Nat! Acad Sci USA 1975;74:1204-83. Dahinden C, Fehr J. Granulocyte activation by endotoxin. I and II.J Immunol 1983;130:857-62, 863-84. Dahinden C, Fehr J. Receptor-directed inhibition of chemotacticfactor-induced neutrophil hyperactivity by pyrazolon derivatives. JClin Invest 1980;66:884-91THE JOURNAL OF INFECTIOUS DISEASES. VOL. 150, NO.1. JULY 1984© 1984 by The University of Chicago. All rights reserved. 0022-1899/84/5001-0031$01.00Mycoplasma pulmonis in the Brains of Rodents:A Rare EventTo ThE EDITOR: We were interested in the article by Hill [1] inwhich she reported that in all rats tested, intranasal inoculationof Mycoplasma pulmonis organisms lead to infection of thebrain 10-14 days later. This communication followed a previousone [2] in which Hill reported recovery of M pulmonis fromthe brains of all mice that either harbored the organisms in thePlease address requests for reprints to Dr. D. Taylor-Robinson, Divi-sion of Sexually Transmitted Diseases, Clinical Research Centre, WatfordRoad, Harrow, Middlesex HAl 3UJ, Great Britain.nasopharynx naturally or that had been inoculated via the nose.These results for mice were in accord with the report by Saitoet al. [3] of very rapid infection of the brains of mice by M pul-monis after the mice had been placed in contact with othersthat had been infected nasally. In our experience, natural trans-mission from nose to nose in mice does not occur readily, andwe found [4] that recovery of M pulmonis from the brain wasa rare event. This was the reason why the report of recovery ofM. pulmonis from the brains of all rats so soon after inocula-tion, apart from being inherently remarkable, sufficientlystimulated our interest to convince us to undertake experimentsof a similar kind. Five- to six-week-old Lac:P male and femalerats (the same strain as that used by Hill) were anesthetized byip inoculation of Hypnorm® (Crown Chemical, u.K.; 0.002

Formylated Chemotactic Peptides Can Mimic the Secondary, Provoking Endotoxin Injection in the Generalized Shwartzman Reaction

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